Hyperandrogenism lies at the pathogenic core of polycystic ovary syndrome (PCOS). PCOS is a highly heritable trait (heritability = 70%) affecting >5 million reproductive age women in the USA, alone. Consequently, PCOS is a costly (~$14 billion/year) women?s health disorder, bestowing infertility, irregular menstrual cycles, polycystic ovaries and a complex array of cardiometabolic and malignant diseases. Progress towards prevention has been hindered by poor understanding of the pathogenic mechanism(s) and complete lack of naturally occurring animal models. Our recent discoveries, however, provide a unique opportunity to break through this impasse. A subset of female Indian rhesus macaques at the Wisconsin National Primate Research Center exhibit naturally occurring hyperandrogenemia (High testosterone, T) accompanied by core features of PCOS: infertility, LH and AMH excess, and insulin resistance. Together with our previous discovery that female macaques exposed in utero to T exhibit PCOS-related traits, these naturally High T macaques provide strong evidence that endogenous female hyperandrogenism programs PCOS-related pathology. In preliminary studies, we employed whole genome sequencing of High T rhesus macaques and contemporary controls and uncovered likely functional missense variants in High T females within previously identified human PCOS candidate genes. Our preliminary findings suggest conservation of genetic pathways and causal mechanisms accompanying hyperandrogenism in female macaques that have the potential to elucidate pathogenic mechanisms. We thus propose to evaluate pedigrees of genealogical female relatives and descendants of High T female Indian rhesus macaques to examine the hypotheses that (1) such relatives represent a population enriched with PCOS-related phenotypes, including but not limited to High T, (2) natural T levels are heritable, and (3) a survey of PCOS candidate genes will illustrate potentially functional variants in High T females. The goal of this R21 proposal is to evaluate the feasibility of developing an Indian rhesus macaque model of PCOS that is both phenotypically relevant to the human disease and results from similar underlying genetic mechanisms. While our prior studies have clearly demonstrated important similarities between High T phenotypes in female rhesus macaques and equivalent traits in women, we cannot at this point document either the heritability of High T in female macaques or the array of mutations segregating among these macaques within 26 known risk genes associated with PCOS in women. No full-scale genetic analysis of the Indian macaque model is warranted without prior evidence of both genetic influences on High T and the potential for parallel genetic mechanisms. This R21 project seeks to determine if these known dimensions of human PCOS are evident in a macaque model of naturally occurring, PCOS-related phenotypes, thereby confirming its unique suitability to acquire profound new insights on the genetic and pathophysiological bases of this reproductive and metabolic disorder.